{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlthough none of the provided abstracts directly mention PRAMEF7, they collectively describe key functions of plakophilin‑2 (PKP2), a desmosomal protein essential for cardiac structure and function. In embryonic development and mature hearts, PKP2 participates in assembling intercellular junctions, thereby ensuring proper cell–cell adhesion and maintaining the mechanical integrity of cardiomyocytes. Disruption of PKP2, as demonstrated in mouse knockout models, leads to defects in heart morphogenesis, disarray of the cytoskeleton, and breakdown of the intercalated discs that normally secure the myocardium’s architecture."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its structural role, PKP2 is crucial for modulating the electrophysiological properties of cardiac cells. Several studies showed that reduced PKP2 expression—whether by gene mutation, knockdown, or haploinsufficiency—leads to sodium current (Iₙₐ) deficits, altered intracellular calcium handling, and impaired electrical synchronization. These electrical alterations are linked to life‐threatening arrhythmias, including Brugada syndrome phenotypes, even in the absence of overt structural cardiomyopathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cellular adhesion and electrical conduction, loss or mutation of PKP2 has been implicated in broader changes in intracellular signaling and gene expression. Deficiency of PKP2 leads to aberrant activation of fibrotic (e.g. TGF‑β/p38 MAPK) pathways, remodeling of intercalated disc components, and dysregulation of focal adhesion and actin cytoskeletal genes. These molecular alterations contribute to the development of arrhythmogenic cardiomyopathy and exacerbate adverse responses during stressors such as endurance exercise, catecholaminergic stimulation, or even substance abuse (as observed in altered prefrontal cortex gene expression profiles). These transcriptomic changes highlight a multifaceted contribution of PKP2 to both the mechanical integrity of cardiac tissue and the regulation of electrical homeostasis under physiological and pathological conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Katja S Grossmann, Christine Grund, Joerg Huelsken, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200402096"}], "href": "https://doi.org/10.1083/jcb.200402096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15479741"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15479741"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Steven Goossens, Barbara Janssens, Stefan Bonné, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A unique and specific interaction between alphaT-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.004713"}], "href": "https://doi.org/10.1242/jcs.004713"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17535849"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17535849"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marina Cerrone, Maartje Noorman, Xianming Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvs218"}], "href": "https://doi.org/10.1093/cvr/cvs218"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22764151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22764151"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Marina Cerrone, Xianming Lin, Mingliang Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.113.003077"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.113.003077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24352520"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24352520"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Marina Cerrone, Jerome Montnach, Xianming Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-017-00127-0"}], "href": "https://doi.org/10.1038/s41467-017-00127-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28740174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28740174"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Adi D Dubash, Chen Y Kam, Brian A Aguado, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.201507018"}], "href": "https://doi.org/10.1083/jcb.201507018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26858265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26858265"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Priyatansh Gurha, Xiaofan Chen, Raffaella Lombardi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.116.308422"}], "href": "https://doi.org/10.1161/CIRCRESAHA.116.308422"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27470638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27470638"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Javier Moncayo-Arlandi, Eduard Guasch, Maria Sanz-de la Garza, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddw213"}], "href": "https://doi.org/10.1093/hmg/ddw213"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27412010"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27412010"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Carolina de Paiva Lima, Daniel Almeida da Silva E Silva, Samara Damasceno, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of control over the ethanol consumption: differential transcriptional regulation in prefrontal cortex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurogenet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/01677063.2017.1349121"}], "href": "https://doi.org/10.1080/01677063.2017.1349121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28714806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28714806"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Joon-Chul Kim, Marta Pérez-Hernández, Francisco J Alvarado, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of Ca"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "2+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "i"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": " Homeostasis and Connexin 43 Hemichannel Function in the Right Ventricle Precedes Overt Arrhythmogenic Cardiomyopathy in Plakophilin-2-Deficient Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.119.039710"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.119.039710"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31315456"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31315456"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Luca Puzzi, Daniele Borin, Priyatansh Gurha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knock Down of Plakophillin 2 Dysregulates Adhesion Pathway through Upregulation of miR200b and Alters the Mechanical Properties in Cardiac Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells8121639"}], "href": "https://doi.org/10.3390/cells8121639"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31847412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31847412"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Marina Cerrone, Grecia M Marrón-Liñares, Chantal J M van Opbergen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Heart J (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/eurheartj/ehab772"}], "href": "https://doi.org/10.1093/eurheartj/ehab772"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34932122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34932122"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Chantal J M van Opbergen, Navratan Bagwan, Svetlana R Maurya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.121.057757"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.121.057757"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35491884"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35491884"}]}]}]}